Active implantable medical device for the diagnosis of cardiac decompensation

ABSTRACT

The disclosure relates to a device including a plurality of electrodes for stimulation of both ventricles with application of an atrioventricular delay and of an interventricular delay, a processor configured to multidimensionally measure an interventricular conduction delay, and monitor the evolution of a patient&#39;s condition. For the multidimensional measurement of the interventricular conduction delay, the device produces stimulation of one of the ventricles and collects, in the other ventricle, two endocardial electrogram signals on separate respective channels, giving two respective temporal components. Both temporal components are combined in one single parametric 2D characteristic representative of the cardiac cycle, and a comparison is made with reference descriptors for deriving an index representative of the evolution of the patient&#39;s condition.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/701,245, filed Sep. 11, 2017, which is a continuation of U.S. patentapplication Ser. No. 15/086,938, now U.S. Pat. No. 9,757,568, filed Mar.31, 2016, which claims the benefit of and priority to French PatentApplication No. 1552843, filed Apr. 2, 2015, each of which isincorporated herein by reference in its entirety.

BACKGROUND

The disclosure relates to “active implantable medical devices” asdefined by Directive 90/385/EEC of 20 Jun. 1990 of the Council of theEuropean Communities.

It more precisely relates to implants that continuously monitor acardiac rhythm and deliver to the heart, if necessary, electrical pulsesto jointly and permanently stimulate the left and right ventricles toresynchronize them, a technique called “CRT” (Cardiac ResynchronizationTherapy) or “BVP” (Bi-Ventricular Pacing).

A CRT pacemaker is disclosed for example in EP 1108446 A1 (Sorin CRM),which describes a device for applying stimulation between the respectivecontractions of the left and right ventricles, creating a variable delaycalled “interventricular delay” (VVD), which is adjusted toresynchronize the contraction of the ventricles with fine optimizationof the patient's hemodynamic status. The VVD can be zero, positive (theleft ventricle is stimulated after the right ventricle) or negative (theright ventricle is stimulated after the left ventricle).

CRT devices also include a “dual chamber operating” mode in which thedevice monitors the ventricular activity after a spontaneous (detectionof an atrial depolarization P wave) or stimulated (application of anatrial pulse A) atrial event. At the same time, the device starts timinga delay called “an atrioventricular delay” (AVD) such that if noventricular spontaneous activity (R wave) has been detected at the endof this period, the device triggers a stimulation of the ventricle(application of a ventricle V pulse).

The general object of the present disclosure is, in this context, tomeasure an interventricular conduction time, i.e., the time intervalbetween a stimuli applied to one of the ventricles and inducedspontaneous contraction in the other ventricle by this stimulation (notethat in this particular configuration of measurement, both ventriclesare no longer stimulated jointly).

Changes to the interventricular conduction time in the long term may bea good indicator of the evolution of the patient's cardiac condition,including the phenomenon known as “cardiac remodeling,” which can bedefined as all the changes of the heart caused in response to a disease,which is generally associated with a worsened prognosis.

The clinical changes may be asymptomatic, it is common that the patientunconsciously adapts its activity to his/her clinical status. Forexample, due to stress, the first heart failure attack symptoms mayappear, leading the patient to reduce his activity to prevent theoccurrence of such crises. The symptoms may not appear anymore becausethe patient changed his/her behavior to avoid them, but the diseasecontinues to progress.

Remodeling occurs, in the long term, by increasing the volume of theleft ventricle, with deterioration in the ejection fraction and of theintraventricular pressure regime due to the decrease of contractilityand/or to excessive pressure downstream and, ultimately, a decrease incardiac output. This may cause serious consequences on the organism bythe progression of heart failure. It is generally only when the heartfailure hinders the patient at rest that he/she will consult or, inextreme cases, be admitted to a hospital.

In summary, due to this self-adjustment, the absence of symptomsexperienced introduces a significant delay between the onset of clinicalchanges and diagnosis of these changes, which is often made too late.

By stimulating the ventricles in a controlled method in at least twopoints, the CRT therapy optimizes the contraction/relaxation cycle, witha direct benefit to facilitate the heart work, which can help stabilizethe remodeling phenomenon, and even counter it (“reverse remodeling”),with an improved prognosis for the patient.

One object of the disclosure is to provide a diagnostic tool, embeddedin a CRT pacemaker, that would provide regular monitoring (e.g. daily)of the patient's condition, especially the evolution of a cardiacremodeling or of a reverse remodeling. The monitoring occurs during anearly stage, to be able to rapidly take appropriate measures, such as achange in the configuration of the CRT therapy, or switching from thisCRT therapy to another one, if is not effective. This avoids theunexpected triggering, in the short or medium term, of a crisis.

The current technique for the evaluation of the patient's condition, andtherefore for the evaluation of the CRT therapy and adjustment of CRTpacing parameters, is evaluated by echocardiography with the measurementof the ventricular volume and the estimate of the characteristic delaysof the systole, in particular the opening delay of the aortic valve.This procedure must, however, be implemented in hospitals and byqualified personnel, as it is long and expensive and cannot be appliedas often as would be useful or necessary without interfering with thepatient's daily life.

The measurement at regular intervals (e.g., daily) of theinterventricular conduction delay and the long term monitoring of thisdata allows a diagnosis of a favorable reverse ventricular remodeling,indicating that the CRT therapy is effective, or vice versa adeleterious ventricular remodeling, indicating a degradation of thepatient's condition.

Automatic analysis techniques from the implantable device have also beenproposed, for example in US 2011/0152660 A1, now U.S. Pat. No.8,249,709, wherein degradation and improving of the condition of thepatient are evaluated from the evolution of the interventricular delay,considered alone or in combination with the evaluation of the patient'sactivity and/or the presence of pulmonary edema. The interventricularconduction delay is measured using endocardial or epicardial left andright ventricular electrodes. However, this method is very sensitive tothe position of the leads, a variation of, for example, 20% of theinterventricular conduction delay being equated with the detection ofthe displacement of a lead. This technique is also sensitive to themethod by which the heart remodels, so that in some cases the measuredventricular conduction delay may not provide the sought remodelinginformation. This may happen especially if no significant change in theconduction delay is observed along the axis of measurement (between thesingle electrode on the right and the single electrode on the left),while according to another axis a much larger variation could have beenobserved.

US 2007/0239037 A1 discloses another method based on the measurement ofthe interventricular conduction delay (as determined by ultrasound)before implantation of the device, which aims to predict the response ofa patient to a CRT therapy. The greater the initial interventricularconduction delay, the higher chance a major remodeling is likely tooccur. However, this is a prediction tool requiring a scan at an initialtime, not a diagnostic tool to assess the long term evolution of apatient's condition, after implantation of the CRT device.

US 2007/0043394 A1, now U.S. Pat. No. 8,494,618, describes a techniquefor diagnosis of heart failure by detection of a variation of theintracardiac impedance at a constant heart rate. The evolution of thisparameter in the long term can infer if the heart remodels or not.However, the measurement of the intracardiac impedance is not a stableparameter in the long term (several weeks or even months), which rendersthe use difficult for diagnostic purposes with a sufficient degree ofreliability.

SUMMARY

According to some embodiments, a CRT implantable device is provided withdiagnosis methods of cardiac remodeling to overcome the aforementioneddrawbacks, and in particular:

To consider at least two measurement axes in order to obtain a morerobust measure of the interventricular delay (a measure designated as“multidimensional measure of interventricular conduction delay”);To avoid long and costly echocardiogram examinations, which provide onlya late diagnosis, often several months after implantation;To quickly and robustly assess patient remodeling to adapt theresynchronization therapy (possible adjustment of the AVD and/or of theVVD);To set up alerts in case of risk of decompensation or of worsenedischemia to prevent hospitalizations and modify in due time thetherapies and treatments; andIn general, to ensure proper delivery and effectiveness of CRT therapy.

More specifically, embodiments of the disclosure provide a cardiacresynchronization therapy device by biventricular stimulation including:

Methods of detection of atrial and ventricular events;Methods of stimulation of the right and left ventricles, with theapplication i) of an atrioventricular delay (AVD) between a spontaneousor stimulated atrial event and stimulation of the right ventricle, andii) an interventricular delay (VVD) between the respective times ofstimulation of the right and left ventricles;Methods of multidimensional measurement of the interventricularconduction delay, counted between a stimulation of the right or the leftventricle and a spontaneous event detected in the left ventricle, orvice versa, or between a stimulation of the right ventricle and aspontaneous event detected between right and left ventricles in the samecardiac cycle; andMethods of monitoring of the evolution of a patient's condition, adaptedto store a history of the measured conduction delays at successive datesand to derive an representative index.

In some embodiments, the methods of multidimensional measuring of theinterventricular conduction delay may include:

Methods adapted for controlling the stimulation and the sensing duringat least one cardiac cycle so as to:

Produce a stimulation of one of the ventricles, and

Collect in the other ventricle, concurrently, on separate respectivechannels, at least two endocardial electrogram (EGM) signals and deriveat least two respective distinct temporal components;

Methods adapted to combine the at least two temporal components in atleast one 2D parametric characteristic representative of the cardiaccycle, based on variations of one of the temporal components as afunction of the other;Methods of analysis, adapted to derive from the 2D characteristic, or anaverage of 2D characteristics collected over successive cardiac cycles,a vector of current intrinsic descriptor parameters of the 2Dcharacteristic; andComparator methods adapted to compare said vector of current descriptorparameters to a homologous vector of reference descriptor parameters forderiving an index representative of the evolution of a patient'scondition.

According to various advantageous embodiments:

The intrinsic descriptor parameters are parameters function of thevelocity vector of the 2D characteristic considered in a plurality ofrespective points of this characteristic, in particular the respectivevalues of the norm of the velocity vector;The comparator methods include methods to operate a cross-correlationbetween i) the vector of current descriptor parameters and ii) thevector of reference descriptor parameters;The index representative of the evolution of a patient's status is thevalue of the delay which maximizes the intercorrelation function betweenthe vector of current descriptor parameters and the vector of referencedescriptor parameters, this delay being, in particular possibly comparedto a predetermined threshold to trigger an alert when this threshold iscrossed;The device further includes methods able to temporarily shorten theatrioventricular delay of the device during the activation of themultidimensional measuring of the ventricular conduction delay;The device further includes methods able to temporarily force theactivation of atrial pacing during the activation of multidimensionalmeasurement of the interventricular conduction delay;The at least two EGM signals concurrently collected on separaterespective channels include:

A unipolar far-field EGM signal (V_(uni)) collected between:

-   -   i) proximal or distal electrode or, where appropriate, an        intermediate electrode or the defibrillation coil of a        ventricular lead located in the not stimulated ventricle and ii)        the metal housing of the generator of the device, or    -   i) a first proximal electrode, or a distal electrode or        defibrillation coil and ii) a second proximal electrode, or a        distal electrode or, where appropriate, an intermediate        electrode or a defibrillation coil, respectively of two separate        ventricular leads located both in the ventricle that is not        stimulated, or    -   i) a first proximal electrode, or a distal electrode or a        defibrillation coil and ii) and a second proximal electrode, or        a distal electrode or an intermediate electrode, respectively of        a right ventricular lead and of a left ventricular lead, and

A bipolar near-field EGM signal collected between:

-   -   i) a distal electrode and ii) a proximal electrode of a        ventricular lead located in the ventricle that is not        stimulated, or    -   i) a defibrillation coil and ii) a distal or proximal electrode        of said ventricular lead, or    -   i) a distal electrode and ii) an intermediate electrode of a        left ventricular lead, or    -   i) a proximal electrode and ii) an intermediate electrode of        said left ventricular lead, or    -   two intermediate electrodes of said left ventricular lead.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features, characteristics and advantages of the presentdisclosure will become apparent to a person of ordinary skill in the artfrom the following detailed description of preferred embodiments of thepresent disclosure, made with reference to the drawings annexed, inwhich like reference characters refer to like elements and in which:

FIG. 1 is a general view showing a CRT device with a generator and rightand left cardiac leads implanted in a heart.

FIG. 2 is an example of EGM signals obtained respectively on bipolarventricular and ventricular unipolar channels of one of the leads ofFIG. 1.

FIG. 3 is an example showing an evolution, in the long term, of unipolarand bipolar EGM signals obtained by stimulating the left ventricle andcollecting the corresponding signal in the right ventricle.

FIG. 4 is another example of EGM, of the same type as in FIG. 3.

FIG. 5 shows a method of combining the bipolar and unipolar signalscollected in a single ventricular cavity to construct a two-dimensional,independent of time, vectogram characteristic.

FIG. 6 is an example of a vectogram obtained for a cardiac cycle sampledat 128 Hz.

FIG. 7 illustrates examples of unipolar and bipolar signals collected inthe right ventricle following a stimulation applied to the leftventricle and the corresponding vectogram constructed from thesesignals.

FIG. 8 is a representation of velocity vectors in an example of asampled vectogram.

FIG. 9 illustrates a principle of a cross-correlation processing,applied between the current descriptor parameters and referencedescriptor parameters of the analyzed vectograms.

FIG. 10 is a schematic diagram illustrating an implementation of anembodiment of the invention.

FIG. 11 is a diagram showing a sequence of steps executed during thepreliminary preparation of references.

FIG. 12 is a diagram showing a sequence of steps performed during apatient follow-up, to determine the evolution of his condition,including a reverse remodeling or a remodeling.

DETAILED DESCRIPTION

An embodiment of the device of the invention will now be described.

Regarding its software aspects, the embodiment of the invention may beimplemented by appropriate programming of the controlling software of aknown stimulator, for example a cardiac pacemaker, including methods ofacquisition of a signal provided by endocardial leads and/or one orseveral implantable sensors.

The embodiment of the invention may notably be applied to implantabledevices, such as that of the Reply, Paradym, Intensia, Paradym RF andPlatinium families, manufactured and commercialized by Sorin CRM,Clamart, France.

These devices include programmable microprocessor circuitry to receive,format and process electrical signals collected by implantableelectrodes, and deliver stimulation pulses to these electrodes. It ispossible to download, by telemetry, software that is stored in memoryand executed to implement the functions of the embodiment of theinvention that are described below. The adaptation of these devices tothe implementation of the functions of the invention is within the skillin the art and will not be described in detail.

A method of the disclosure is implemented primarily by software, byappropriate algorithms automatically and repeatedly executed by amicrocontroller or a digital signal processor. For the sake of clarity,the various processing applied are broken down and schematically by anumber of distinct functional blocks, but this representation, however,is only for illustrative purposes, these circuits include commonelements and correspond in practice to a plurality of functionsgenerally performed by the same software.

FIG. 1 illustrates a stimulation configuration wherein a pulse generator10 is associated with a first lead 12 located in the right ventricle 14.A head of the lead includes two electrodes, namely a distal electrode(tip) 16 and a proximal electrode (ring) 18. A second lead 20 isprovided with distal 22 and proximal 24 electrodes for atrial detectionlocated at the right atrium 26 for the detection of signals in thiscavity and to optionally apply atrial stimulation.

To allow bi-ventricular pacing, in particular to restore thesynchronization between the two ventricles, the device is provided witha third lead 28, for example a lead disposed in the coronary network,including one or more electrodes 30, 32 disposed in the vicinity of theleft ventricle 34. In addition to the illustrated distal and proximalelectrodes 30, 32, the left lead may also include one or moreintermediate electrodes located in a median position between theelectrodes 30 and 32.

It is thus possible to ensure the simultaneous stimulation, or with acontrolled slight temporal shift (interventricular delay VVD), of boththe right and left ventricles to restore the synchronization betweenthese two cavities and improve overall patient hemodynamics. The rightventricular lead 12 may also be provided with a ventricular coil 36forming a defibrillation electrode and also be able to collect anendocardial signal (this coil being also able to replace the proximalring electrode 18).

With specific regard to the stimulation of the left ventricle, it ispossible to use a bipolar configuration (between the two electrodes 30and 32 of the lead 28) or unipolar configuration (between one of theelectrodes 30 or 32 and the can housing) of the generator 10. The twocorresponding “stimulation vectors” are referenced 38 and 40 in FIG. 1.These same vectors can also be used for collecting a signal of leftventricular depolarization. Note that in the case of a multipolar lead,a large number of bipolar and unipolar possible vectors are possible,defined from each of the electrodes.

One object of the disclosure is to provide monitoring of cardiacremodeling, from the measurement of an interventricular conductiondelay:

When the ventricular volume decreases (reverse remodeling, beneficial tothe patient), the conduction delay between the ventricles should beshortened;Conversely, when the heart expands (deleterious remodeling), theconduction delay between the ventricles should increase.

More specifically, to overcome the drawbacks of known techniques thathave been recalled in the introduction, the disclosure proposes tocombine two endocardial electrogram signals (EGM) from the sameventricular cavity, for example from the right ventricle. These signalsresult from the depolarization produced through the application of astimulation on the other ventricle (the left ventricle in this example).

As shown in FIG. 1, the EGMs thus collected in the right ventricle mayinclude:

A right ventricular component V_(bip) derived from a bipolar near-fieldEGM signal collected between the distal electrode 16 and the proximalelectrode 18 of the right ventricular lead 12, andAnother right ventricular component V_(uni) derived from a unipolarfar-field EGM signal collected between the defibrillation coil 36 of theright ventricular lead 12 and the metal housing of the generator 10.

FIG. 2 illustrates an example of V_(bip) and V_(uni) EGM plotsrespectively observed on the ventricular bipolar channel and on theventricular unipolar channel of the configuration of FIG. 1.

Other configurations can be used, from far-field type signals (e.g.,between one of the electrodes 16 or 18 and the housing 10) andnear-field type signals from the non-stimulated ventricular cavity,namely the right ventricle in the example shown.

It could also be considered, in a reverse configuration, to stimulatethe right ventricle and to collect bipolar and unipolar EGMs in the leftventricle. The bipolar component may then be collected for examplebetween electrodes 30 and 32 of the left ventricular lead 28 (asreferenced at 38), and the unipolar component between the tip electrode30 (or the electrode ring 32) and the can housing of the generator 10,as referenced at 40. Alternatively, the unipolar component may also becollected between the tip electrode 30 (or the ring electrode 32) of theleft ventricular lead 28 and the coil winding 36 of the rightventricular lead 12 as referenced at 42.

FIGS. 3 and 4 correspond to two examples of V_(bip) and V_(uni) EGMsignals collected with the configuration of FIG. 1, as they appear atthe time of implantation (curve M0), three months after implantation(curve M3) and one year after implantation (M12 curve).

As can be seen, the shape of these signals changes over time, but forexample in the case of FIG. 3 the unipolar signal does not reallyprovide any information on the evolution in time of the conductiondelay, while the bipolar signal V_(bip) contains much more meaningfulinformation. Conversely, in the case of FIG. 4, the response is verylate in the bipolar signal V_(bip) and it is the unipolar channel(between the coil winding 36 and the can housing 10 of the generator),which provides, in a more discriminating method, the requiredinformation.

To overcome this drawback, the disclosure proposes to combine bothbipolar and unipolar components containing a unique characteristic, andmore broadly, all available information in order to conduct a completeand robust assessment of the patient's condition over time.

This combination of both bipolar and unipolar signals is designed as a“heart loop” or “vectogram” (VGM), which is the representation in atwo-dimensional space of one of the two EGM signals (on the ordinate)relative to one another (on the abscissa). Each cardiac cycle is thenrepresented by a vectogram in the {V_(bip), V_(uni)} plan thus definedwhich thus ignore the temporal dimension.

It is emphasized that this “vectogram” (VGM), which is obtained fromelectrogram signals (EGM) from intracardiac leads, should not beconfused with the “vectocardiogram” (VCG), which is itself obtained fromelectrocardiogram (ECG) signals from external electrodes placed on thepatient's chest.

The construction of a VGM and its analysis to quantify cardiac data aredescribed for example in Milpied et al., “Arrhythmia Discrimination inImplantable Cardioverter Defibrillators Using Support Vector MachinesApplied to a New Representation of Electrograms,” IEEE Transactions onBiomedical Engineering, June 2011, 58 (6): 1797-1803.

Analysis of a VGM for different purposes than those of the disclosurehas already been proposed in particular from EP 2105843 (Sorin CRM) fordiscriminating between ventricular and supraventricular tachycardia,from EP 2324885 A1 (Sorin CRM) for invalidating a capture test in caseof fusion, that is to say stimulation simultaneously triggered tospontaneous depolarization, from EP 2368493 A1 (Sorin CRM) fordiscriminating noise artifacts for the validation or invalidation ofcardiac cycles to be analyzed, from EP 2742971 A1 (Sorin CRM) fordetermining the presence or absence of an evoked wave induced by thestimulation of a cavity, or by the EP 2742973 A1 (Sorin CRM) fordetecting the possible presence of an anodal stimulation phenomenon.

Specifically, as shown in FIG. 5, the collected EGM signals V_(uni)(t)and V_(bip)(t) are sampled, and the successive samples of the twocomponents are stored and then combined to produce a parametric curve(the VGM characteristic) of the type VGM=(V_(bip)(t), V_(uni)(t)) or{x=V_(bip)(t), y=V_(uni)(t)}.

This curve is a curve parameterized by time, plotted on the basis ofchanges in one of the temporal components (V_(uni)) as a function of theother (V_(bip)). It is a vectogram (VGM) representative of the cardiaccycle to be analyzed, and is also referred to as “parametric 2Dcharacteristic”. It graphically shows the shape of a loop, wherein thetime only appears in the manner in which the loop is traversed over thecycle duration.

Note that the “two-dimensional” (2D) analysis discussed here should notbe understood in itself in a limiting way. The invention can indeed beapplied equally to an analysis in higher order multi-dimensional space(3D or more), by extrapolating the teachings of the present descriptionto a situation wherein EGM signals from the same cavity is collectedsimultaneously on three channels or more.

In practice, as shown in FIG. 6, sampling produces an open polygon VGMwherein each vertex corresponds to a sampling point of the measurementsignal V_(uni) and V_(bip) EGM. In the example of FIG. 6, sampling iscarried out at a frequency of 128 Hz, which gives about 20 to 25measurement points, which are values that can be stored for analysis.

FIG. 7 illustrates more precisely the shape of V_(uni) and V_(bip)components in the case of a single stimulation of the left ventricle,the VGM being constructed with V_(bip) and V_(uni) EGMs collected in theright ventricle. In this figure it can be seen that the signal peakStimA corresponds to the atrial stimulation and StimVG corresponds tothe ventricular stimulation, the interventricular conduction delay ΔVVcan also be seen.

For analysis, the VGM is recorded from the instant of the ventricularstimulation peak StimVG. Advantageously, the atrioventricular delay AVDseparating the atrial stimulation from the ventricular stimulation isreduced during the time of the measurement to a minimum value, forexample AVD=30 ms, to ensure that there will be no fusion phenomenonwith spontaneous conduction in the ventricle where the detection takesplace (the right ventricle). The atrium can also be stimulated duringthe time of measurement to artificially lengthen the PR interval andprevent fusion.

The VGM is built periodically, for example once a day or once a week,under stable conditions (slow sinus rhythm, preferably overnight), to bestored and compared to a reference VGM created initialization therapy,and possibly updated in case of an emergency or a failure, or manuallyby the practitioner during a follow-up visit.

Advantageously, the VGM characteristic is stored as a vector ofintrinsic descriptor parameters, describing in a condensed form theimportant features that will be used to analyze the VGM curve.

Advantageously, these intrinsic descriptor parameters of the VGM are, asshown in FIG. 8, the successive values of the magnitude of the velocityat which the VGM is traversed, calculated at each point on the VGM. At agiven point, velocity is a vector data (velocity being defined by itsorientation and magnitude) which for a sampled characteristic can becalculated from the previous point and the next point on the curve.

In practice, for the purpose, namely the monitoring of the evolution ofthe interventricular conduction delay, it appears that the velocitymagnitude is a sufficient parameter, allowing significant savings interms of computation and memory resources, a given VGM being simplystored in the form of a series (vector) of representative intrinsicdescriptor parameters of the current VGM built at a given time.

To compare the current VGMs (stored as a vector of intrinsicdescriptors) with a reference VGM (stored as a homologous vector ofdescriptor parameters), a cross-correlation between these two descriptorvectors is advantageously performed.

FIG. 9 schematically represents such a cross-correlation. The schematicfunction f corresponds to the vector of the intrinsic descriptorparameters of the reference VGM and the function g to the intrinsicdescriptor parameters of the current VGM to be compared. Thecross-correlation f*g produces a value τ of an offset to be applied toone of the descriptor parameter vectors to be aligned with the otherdescriptor vector.

The value of the delay τ which minimizes the cross-correlation functionf*g(τ) is regarded as an index representative of the patient's conditionat the time of construction of the considered current VGM:

If this delay τ is negative, this means that a delay should be appliedto the current VGM to maximize the cross-correlation function, theconduction time being shortened. If this value exceeds a predeterminedthreshold, for example τ<−10 ms, it is then considered that the patientis in the presence of a reverse, beneficial, remodeling;Conversely, if the delay τ is positive, it means that the delay shouldbe applied to the reference VGM and the conduction time has lengthened,indicating a worsening of the patient's condition. Similarly, if thevalue exceeds a predetermined threshold, for example τ>10 ms, it isconsidered that remodeling occurred.

FIG. 10 very generally illustrates a method in which the device of anembodiment of the disclosure is implemented.

From the collected bipolar and unipolar EGMs, a VGM is constructed(block 100). First, reference is made (block 102, detailed FIG. 11) andstored in memory (block 104). Similarly, periodically (e.g., daily) acurrent VGM is constructed and compared to the stored reference (block106) to derive an indicator of the evolution of the patient's condition(remodeling, reverse remodeling, or non-scalable state).

The creation of the reference (block 102 of FIG. 10) is operated asshown in FIG. 11.

This reference is created from a plurality of representative cardiaccycles (absence of artifact, extrasystole, fusion, etc.), for examplex=2 to 5 cardiac cycles, for each of which the VGM is constructed andthe descriptor parameter vector is calculated (block 108). These dataare then averaged (block 110) or, alternatively, one of the mostrepresentative cardiac cycles is selected to be the reference (block112). From the averaged or selected VGM, the reference is validated(block 114), by comparing it to each cycle collected in step 108, so asto verify that the difference between this reference and each of theother cycles remains within acceptable limits.

FIG. 12 illustrates a sequence of various test operations of the currentVGM (block 106 of FIG. 10) performed at regular intervals, for exampleevery day.

The patient is stimulated for several cardiac cycles no longer inbiventricular CRT stimulation, but in left ventricular stimulation only,with an AVD minimized to avoid fusion (e.g., AVD=30 ms) and a detectionof the evoked wave in the right ventricle, according to both the bipolarV_(bip) component and unipolar V_(uni) component (block 118).

If no reference is available at this step (that is to say just afterimplantation), or if the stimulation parameters were modified, areference corresponding to the current state of the patient should becreated. To do this, a reference VGM is constructed (in the methodexplained above with reference to FIG. 11), for example, in the case ofsampling at 128 Hz, for a duration of approximately 125 ms after atrialstimulation, from the sample points 10-26 (block 120). The values of thevelocity magnitude at each point of the VGM are then calculated andstored for constructing a vector of current intrinsic descriptorparameters of the VGM, which in this W example consists of a vector of17 values (block 122).

If, after step 118, a reference is available in memory, the deviceconstructs the current VGM (block 124) and constitutes the correspondingvector of current intrinsic descriptor parameters (block 126) in thesame method as in blocks 120 and 122 described above.

A cross-correlation is made between the current descriptor parametersfrom the block 126 and the reference descriptor parameters that werepreviously calculated at block 122 to obtain the τ delay value thatmaximizes the cross-correlation function between the vector of commondescriptor parameters and the vector reference descriptor parameters(block 128).

If this delay value τ is positive and greater than a given threshold,for example τ>10 ms, this indicates that there was decompensation andremodeling (block 130), revealing a worsening of the patient'scondition. An alert can be triggered so that appropriate action can betaken without delay (e.g., modification of CRT pacing parameters, takingmedication, etc.).

If the delay τ is relatively low, for example −10 ms<τ<10 ms, it isconsidered that the patient's condition has not changed significantly(block 132).

Finally, for negative values oft below a given threshold, for exampleτ<−10 ms, it is considered that there was reverse remodeling (block 134)and thus improvement of the patient's condition.

What is claimed is:
 1. An implantable medical device comprising: amemory for storing instructions; and a processor configured to executethe instructions to: deliver stimulation via a plurality of electrodesto one of the right or left ventricles; collect, in the other ventricle,at least two EGM signals of endocardial electrogram and derive at leasttwo respective distinct temporal components; combine the at least twotemporal components in at least one parametric 2D characteristicrepresentative of the cardiac cycle; and analyze, from the 2Dcharacteristic, or from an average of 2D characteristics collected oversuccessive cardiac cycles, a vector of current intrinsic descriptorparameters of the 2D characteristic to determine the patient'scondition.
 2. The device of claim 1, wherein said current intrinsicdescriptor parameters are parameters of the velocity vector of the 2Dcharacteristic, considered in a plurality of respective points of the 2Dcharacteristic.
 3. The device of claim 2, wherein said parameters of thevelocity vector are the respective values of the magnitude of thevelocity vector.
 4. The device of claim 1, wherein the processor isfurther configured to analyze said vector of current intrinsicdescriptor parameters by comparing said vector to a homologous vector ofreference descriptor parameters to derive an index representative of theevolution of the patient's condition.
 5. The device of claim 4, whereincomparing said vector of current intrinsic descriptor parameterscomprises operating a cross-correlation between i) the vector of thecurrent intrinsic descriptor parameters and ii) the vector of thereference descriptor parameters.
 6. The device of claim 5, wherein saidindex representative of the evolution of a patient's condition is avalue of a delay (τ) which maximizes an intercorrelation functionbetween the vector of the current intrinsic descriptor parameters andthe vector of the reference descriptor parameters.
 7. The device ofclaim 6, wherein the processor is further configured to compare thedelay with a predetermined threshold and trigger an alert if thepredetermined threshold is crossed.
 8. The device of claim 1, whereinthe at least two EGM signals are collected concurrently on separaterespective channels.
 9. The device of claim 8, wherein the at least twoEGM signals collected concurrently on separate respective channelsinclude a unipolar EGM far-field signal and a near-field EGM bipolarsignal.
 10. The device of claim 9, wherein the unipolar EGM far-fieldsignal is collected between a first location comprising at least one ofa proximal electrode, a distal electrode, an intermediate electrode, ora defibrillation coil electrode of a ventricular lead located in anunstimulated ventricle and a second location comprising a metal housinggenerator of the device.
 11. The device of claim 9, wherein the unipolarEGM far-field signal is collected between a first location comprising atleast one of a first proximal electrode, a first distal electrode, or afirst defibrillation coil electrode of a first ventricular lead and asecond location comprising at least one of a second proximal electrode,a second distal electrode, an intermediate electrode or a seconddefibrillation coil electrode of a second ventricular lead, wherein boththe first and the second ventricular leads are located in anunstimulated ventricle.
 12. The device of claim 9, wherein the unipolarEGM far-field signal is collected between a first location comprising atleast one of a first proximal electrode, a first distal electrode, or afirst defibrillation coil electrode of a first ventricular lead and asecond location comprising at least one of a second proximal electrode,a second distal electrode, or an intermediate electrode of a secondventricular lead, wherein the first ventricular lead is located in theright ventricle and the second ventricular lead is located in the leftventricle.
 13. The device of claim 9, wherein the near-field EMG bipolarsignal is collected between a distal electrode and a proximal electrodeof a ventricular lead located in an unstimulated ventricle.
 14. Thedevice of claim 9, wherein the near-field EMG bipolar signal iscollected between a defibrillation coil and at least one of a proximalelectrode or a distal electrode of a ventricular lead.
 15. The device ofclaim 9, wherein the near-field EMG bipolar signal is collected betweena distal electrode and an intermediate electrode of a left ventricularlead.
 16. The device of claim 9, wherein the near-field EMG bipolarsignal is collected between a proximal electrode and an intermediateelectrode of a left ventricular lead.
 17. The device of claim 9, whereinthe near-field EMG bipolar signal is collected between a firstintermediate electrode and a second intermediate electrode of a leftventricular lead.
 18. The device of claim 1, further comprising theelectrodes.
 19. A method of cardiac resynchronization by biventricularstimulation, comprising: delivering stimulation via a plurality ofelectrodes to the right and left ventricles; collecting, in the otherventricle, at least two EGM signals of endocardial electrogram andderive at least two respective distinct temporal components; combiningthe at least two temporal components in at least one parametric 2Dcharacteristic representative of the cardiac cycle; analyzing, from the2D characteristic, or from an average of 2D characteristics collectedover successive cardiac cycles, a vector of current intrinsic descriptorparameters of the 2D characteristic to determine the patient'scondition.
 20. The method of claim 19, wherein the analysis furthercomprises comparing said vector of current intrinsic descriptorparameters to a homologous vector of reference descriptor parameters toderive an index representative of the evolution of the patient'scondition.